Project Summary: The long-term goal of this study is to develop a novel biomimetic retinal neural interface for treating vision loss from incurable blinding diseases such as age-related macular degeneration and retinitis pigmentosa that affect millions of Americans. Vision loss in these diseases is due to gradual death of light-sensitive photoreceptor cells in the retina at the back of the eye. The photoreceptors normally convert the visual stimuli into electrochemical signals that are relayed to the brain for the perception of sight through a complex neural network. Their degeneration impairs the ability of the retina to detect light and initiate vision. Retinal prostheses seeking to restore the lost function of photoreceptors by stimulating surviving cells with electrical current are emerging as a promising option for treating such blindness. However, they have difficulty restoring naturalistic vision and visual acuity below the legal blindness limit. The main barrier to achieving better visual acuity with current retinal prostheses is the stimulus agent because electrical current is an unnatural stimulus for cells. To overcome this barrier, we propose a fundamentally different approach: a retinal prosthesis that transforms visual stimuli into chemical stimuli just like natural photoreceptors. Stimulating live retinal tissues in a dish with the brain chemical glutamate has been shown to mimic its natural activation following visual stimulation. Therefore, artificially stimulating the retina with glutamate delivered through a prosthetic device implanted in the back of the eye could potentially circumvent the limitations of current retinal prostheses. Our goal in this R21 application is to innovate and develop such a device called artificial retinal chemical synapse (ARCS) chip that stimulates surviving retinal cells with glutamate directly in response to visual stimuli just like photoreceptors through an interdisciplinary collaboration, combining the varied fields of microsystems, optofluidics, biology and visual neuroscience. The ARCS chip is an implantable optofluidic device that would deliver therapeutic amounts of glutamate into the retina wirelessly and spatiotemporally in response to natural light through an array of microscopic organic solar cell-powered hollow microneedles. This technology will obviate the need for any auxiliary power, complex electronics to capture and process images and to detect the direction of gaze as required in current retinal prostheses. We will develop this enabling technology through the following two specific aims: 1) Design and fabricate a prototype ARCS chip. We will develop an optofluidic device for light-controlled spatiotemporal delivery of glutamate into the retina. 2) Evaluate the neural interface functionality of the prototype ARCS chip. We will test the ability of the optofluidic device to biomimetically stimulate the retina by interfacing it with a piece of retinal tissue explanted from a photoreceptor degenerated rat. The development of this technology represents an important first step toward animal and clinical investigations of a chemical retinal prosthesis.